nNOS gene deletion exacerbates pathological left ventricular remodeling and functional deterioration after myocardial infarction

Dana Dawson, Craig A Lygate, Mei Hua Zhang , Karen Hulbert, Stefan Neubauer, Barbara Casadei

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Background: The neuronal isoform of nitric oxide synthase (nNOS) has been implicated in the regulation of basal and ß-adrenergic inotropy in normal and chronically infarcted hearts. Furthermore, myocardial nNOS expression and activity increase in failing hearts, raising the possibility that nNOS may influence left ventricular (LV) remodeling progression and functional deterioration after myocardial infarction (MI)
Methods and Results: We compared LV remodeling at 1, 4, and 8 weeks after MI in nNOS-knockout mice (nNOS-/-) and their wild-type (WT) littermates matched for infarct size by using a highly accurate 3-dimensional echocardiographic technique. Basal LV hemodynamics and the inotropic response to dobutamine infusion (4 and 16 ng · g-1 · min-1) were also evaluated 8 weeks after MI. Sham-operated nNOS-/- mice showed enhanced basal LV contractility (P<0.03 versus WT, as evaluated by preload-recruitable stroke work) but an attenuated inotropic response to dobutamine infusion (P<0.01 versus WT). Both basal and ß-adrenergic LV relaxations were significantly impaired in nNOS-/- mice. Survival after MI did not differ between groups. However, nNOS-/- mice developed a faster and more severe LV dilation compared with WT mice (P<0.05 for both end-systolic and end-diastolic volume indices). WT mice maintained a positive inotropic response to dobutamine 8 weeks after MI. In contrast, infarcted nNOS-/- mice responded to dobutamine with a dramatic fall in LV contractility (P<0.01 for preload-recruitable stroke work).
Conclusions: nNOS plays a crucial role in preventing adverse LV remodeling and maintaining myocardial ß-adrenergic reserve after MI. Taken together, our findings suggest that upregulation of myocardial nNOS in infarcted hearts may be an important adaptive mechanism.
Original languageEnglish
Pages (from-to)3729-3737
Number of pages9
JournalCirculation
Volume112
Issue number24
DOIs
Publication statusPublished - 2005

Fingerprint

Nitric Oxide Synthase Type I
Ventricular Remodeling
Gene Deletion
Protein Isoforms
Myocardial Infarction
Dobutamine
Adrenergic Agents
Stroke
Knockout Mice
Dilatation
Up-Regulation
Hemodynamics

Keywords

  • adaptation, physiological
  • animals
  • animal disease models
  • dobutamine
  • echocardiography, three-dimensional
  • female
  • gene deletion
  • male
  • mice
  • knockout mice
  • myocardial contraction
  • myocardial infarction
  • nitric oxide synthase type I
  • receptors, adrenergic, beta
  • survival rate
  • ventricular dysfunction, left
  • ventricular remodeling
  • hemodynamics

Cite this

nNOS gene deletion exacerbates pathological left ventricular remodeling and functional deterioration after myocardial infarction. / Dawson, Dana; Lygate, Craig A; Zhang , Mei Hua; Hulbert, Karen; Neubauer, Stefan; Casadei, Barbara.

In: Circulation, Vol. 112, No. 24, 2005, p. 3729-3737.

Research output: Contribution to journalArticle

Dawson, Dana ; Lygate, Craig A ; Zhang , Mei Hua ; Hulbert, Karen ; Neubauer, Stefan ; Casadei, Barbara. / nNOS gene deletion exacerbates pathological left ventricular remodeling and functional deterioration after myocardial infarction. In: Circulation. 2005 ; Vol. 112, No. 24. pp. 3729-3737.
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T1 - nNOS gene deletion exacerbates pathological left ventricular remodeling and functional deterioration after myocardial infarction

AU - Dawson, Dana

AU - Lygate, Craig A

AU - Zhang , Mei Hua

AU - Hulbert, Karen

AU - Neubauer, Stefan

AU - Casadei, Barbara

PY - 2005

Y1 - 2005

N2 - Background: The neuronal isoform of nitric oxide synthase (nNOS) has been implicated in the regulation of basal and ß-adrenergic inotropy in normal and chronically infarcted hearts. Furthermore, myocardial nNOS expression and activity increase in failing hearts, raising the possibility that nNOS may influence left ventricular (LV) remodeling progression and functional deterioration after myocardial infarction (MI) Methods and Results: We compared LV remodeling at 1, 4, and 8 weeks after MI in nNOS-knockout mice (nNOS-/-) and their wild-type (WT) littermates matched for infarct size by using a highly accurate 3-dimensional echocardiographic technique. Basal LV hemodynamics and the inotropic response to dobutamine infusion (4 and 16 ng · g-1 · min-1) were also evaluated 8 weeks after MI. Sham-operated nNOS-/- mice showed enhanced basal LV contractility (P<0.03 versus WT, as evaluated by preload-recruitable stroke work) but an attenuated inotropic response to dobutamine infusion (P<0.01 versus WT). Both basal and ß-adrenergic LV relaxations were significantly impaired in nNOS-/- mice. Survival after MI did not differ between groups. However, nNOS-/- mice developed a faster and more severe LV dilation compared with WT mice (P<0.05 for both end-systolic and end-diastolic volume indices). WT mice maintained a positive inotropic response to dobutamine 8 weeks after MI. In contrast, infarcted nNOS-/- mice responded to dobutamine with a dramatic fall in LV contractility (P<0.01 for preload-recruitable stroke work). Conclusions: nNOS plays a crucial role in preventing adverse LV remodeling and maintaining myocardial ß-adrenergic reserve after MI. Taken together, our findings suggest that upregulation of myocardial nNOS in infarcted hearts may be an important adaptive mechanism.

AB - Background: The neuronal isoform of nitric oxide synthase (nNOS) has been implicated in the regulation of basal and ß-adrenergic inotropy in normal and chronically infarcted hearts. Furthermore, myocardial nNOS expression and activity increase in failing hearts, raising the possibility that nNOS may influence left ventricular (LV) remodeling progression and functional deterioration after myocardial infarction (MI) Methods and Results: We compared LV remodeling at 1, 4, and 8 weeks after MI in nNOS-knockout mice (nNOS-/-) and their wild-type (WT) littermates matched for infarct size by using a highly accurate 3-dimensional echocardiographic technique. Basal LV hemodynamics and the inotropic response to dobutamine infusion (4 and 16 ng · g-1 · min-1) were also evaluated 8 weeks after MI. Sham-operated nNOS-/- mice showed enhanced basal LV contractility (P<0.03 versus WT, as evaluated by preload-recruitable stroke work) but an attenuated inotropic response to dobutamine infusion (P<0.01 versus WT). Both basal and ß-adrenergic LV relaxations were significantly impaired in nNOS-/- mice. Survival after MI did not differ between groups. However, nNOS-/- mice developed a faster and more severe LV dilation compared with WT mice (P<0.05 for both end-systolic and end-diastolic volume indices). WT mice maintained a positive inotropic response to dobutamine 8 weeks after MI. In contrast, infarcted nNOS-/- mice responded to dobutamine with a dramatic fall in LV contractility (P<0.01 for preload-recruitable stroke work). Conclusions: nNOS plays a crucial role in preventing adverse LV remodeling and maintaining myocardial ß-adrenergic reserve after MI. Taken together, our findings suggest that upregulation of myocardial nNOS in infarcted hearts may be an important adaptive mechanism.

KW - adaptation, physiological

KW - animals

KW - animal disease models

KW - dobutamine

KW - echocardiography, three-dimensional

KW - female

KW - gene deletion

KW - male

KW - mice

KW - knockout mice

KW - myocardial contraction

KW - myocardial infarction

KW - nitric oxide synthase type I

KW - receptors, adrenergic, beta

KW - survival rate

KW - ventricular dysfunction, left

KW - ventricular remodeling

KW - hemodynamics

U2 - 10.1161/CIRCULATIONAHA.105.539437

DO - 10.1161/CIRCULATIONAHA.105.539437

M3 - Article

VL - 112

SP - 3729

EP - 3737

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 24

ER -